Downregulation of Renal G Protein–Coupled Receptor Kinase Type 4 Expression via Ultrasound‐Targeted Microbubble Destruction Lowers Blood Pressure in Spontaneously Hypertensive Rats

Abstract

Background G protein–coupled receptor kinase type 4 ( GRK 4) plays a vital role in the long‐term control of blood pressure (BP) and sodium excretion by regulating renal G protein–coupled receptor phosphorylation, including dopamine type 1 receptor (D 1 R). Ultrasound‐targeted microbubble destruction ( UTMD ) is a promising method for gene delivery. Whether this method can deliver GRK 4 small interfering RNA (si RNA) and lower BP is not known. Methods and Results BP, 24‐hour sodium excretion, and urine volume were measured after UTMD ‐targeted GRK 4 si RNA delivery to the kidney in spontaneously hypertensive rats. The expression levels of GRK 4 and D 1 R were determined by immunoblotting. The phosphorylation of D 1 R was investigated using immunoprecipitation. The present study revealed that UTMD ‐mediated renal GRK 4 si RNA delivery efficiently reduced GRK 4 expression and lowered BP in spontaneously hypertensive rats, accompanied by increased sodium excretion. The increased sodium excretion might be accounted for by the UTMD regulation of D 1 R phosphorylation and function in spontaneously hypertensive rats. Further analysis showed that, although UTMD had no effect on D 1 R expression, it reduced D 1 R phosphorylation in spontaneously hypertensive rats kidneys and consequently increased D 1 R‐mediated natriuresis and diuresis. Conclusions Taken together, these study results indicate that UTMD ‐targeted GRK 4 si RNA delivery to the kidney effectively reduces D 1 R phosphorylation by inhibiting renal GRK 4 expression, improving D 1 R‐mediated natriuresis and diuresis, and lowering BP, which may provide a promising novel strategy for gene therapy for hypertension.